Four children with familial hyperlyssnemia have been investigated in this laboratory. From results thus obtained and from information reported elsewhere, it can be shown that a deficiency of lysine:ketoglutarate reductase activity in these patients prevents them from converting lysine to saccharopine. Similarly, an alternate path of lysine catabolism by way of formation of pipecolic acid has been demonstrated for them. Further studies are designed to: (1) Continue current serial clinical and biochemical studies on the 3 living subjects with familial hyperlysinemia in order to monitor the natural history of this condition. (2) Determine levels of lysine and lysine metabolites in tissues of one child who died. (3) Determine, in vitro, capacities of liver and kidney from this child to convert L-lysine to pipecolic acid. (4) Assess the capacity of young infants and children to handle oral loads of lysine in order to evaluate the various paths available to them for lysine metabolism. (5) Establish if pipecolic acid is a normal constituent of human serum. (6) Look for additional evidence to support the presence in hyperlysinemics of a 'lysine urea cycle.' (7) Re- examine members of the parenal sibships of three of these children for lesser degrees of hyperlysinemia using precise ion-exchange methods not available at the time the original screening was done.